Aldose reductase (AR) is believed to play a major role in the secondary complications of diabetes. Studies in this laboratory have focused on the regulatory properties, potential inhibitor sites, and overall structure of aldose reductase. Better knowledge of these aspects of the protein should help in regulating the undesirable effects of this enzyme. For example, expression of large amounts of recombinant AR protein now set the stage for x-ray crystallography and site-directed mutagenesis studies with the goal of localizing the important functional sites of the molecule. Regulation of the gene for AR is also being studied. Controlling the expression of AR at the gene level may limit the effect this protein has on the accumulation of sorbitol in hyperglycemic conditions. Rat lens and human placenta AR have been expressed in Escherichia coli. The recombinant proteins have been purified and have immunological and kinetic properties similar to their respective tissue AR, including the same substrate and inhibitor profiles. Characterization of the promoter area of the AR gene shows one TATA and two CCAAT boxes and an approximately 14 kb gene. The nucleotide sequence is nearly complete. We have found that AR is induced under hypertonic conditions in several cell types, including cultured dog lens epithelial cells and dog kidney endothelial cells. Recently, we have also found an 8- to 16-fold induction of alphaB-crystallin in these same cells grown in hypertonic media (550 mosM). It appears that AR and alphaB-crystallin are osmotic stress proteins.